Blurring in patients with temporal lobe epilepsy: clinical, high

Transcription

Brain Advance Access published June 22, 2012
doi:10.1093/brain/aws149
Brain 2012: Page 1 of 13
| 1
BRAIN
A JOURNAL OF NEUROLOGY
Blurring in patients with temporal lobe epilepsy:
clinical, high-field imaging and
ultrastructural study
1
2
3
4
5
Clinical Epileptology and Experimental Neurophysiology Unit, Fondazione IRCCS, Istituto Neurologico ‘C. Besta’, 20133 Milan, Italy
Neuroradiological Unit, Fondazione IRCCS, Istituto Neurologico ‘C. Besta’, 20133 Milan, Italy
Neuropathology Unit, Fondazione IRCCS, Istituto Neurologico ‘C. Besta’, 20133 Milan, Italy
Scientific Department, Fondazione IRCCS, Istituto Neurologico ‘C. Besta’, 20133 Milan, Italy
Department of Bioengineering, Politecnico di Milano, 20133 Milan, Italy
Correspondence to: Rita Garbelli,
Clinical Epileptology and Experimental Neurophysiology Unit,
Fondazione IRCCS Istituto Neurologico C. Besta,
via Amadeo 42,
20133 Milano,
Italy
E-mail: [email protected]
Magnetic resonance imaging-positive temporal lobe atrophy with temporo-polar grey/white matter abnormalities (usually called
‘blurring’) has been frequently reported in patients with temporal lobe epilepsy associated with hippocampal sclerosis. The poor
distinction of grey and white matter has been attributed to various causes, including developmental cortical abnormalities,
gliosis, myelin alterations, a non-specific increase in temporal lobe water content and metabolic/perfusion alterations. However,
there is still no consensus regarding the genesis of these abnormalities and no histopathological proof for a structural nature of
magnetic resonance imaging changes. The aim of this study was to investigate the pathological substrate of temporo-polar
blurring using different methodological approaches and evaluate the possible clinical significance of the abnormalities. The
study involved 32 consecutive patients with medically intractable temporal lobe epilepsy and hippocampal sclerosis who underwent surgery after a comprehensive electroclinical and imaging evaluation. They were divided into two groups on the basis of
the presence/absence of temporo-polar blurring. Surgical specimens were examined neuropathologically, and selected samples
from both groups underwent high-field 7 T magnetic resonance imaging and ultrastructural studies. At the clinical level, the two
groups were significantly different in terms of age at epilepsy onset (earlier in the patients with blurring) and epilepsy duration
(longer in the patients with blurring). Blurring was also associated with lower neuropsychological test scores, with a significant
relationship to abstract reasoning. On 7 T magnetic resonance image examination, the borders between the grey and white
matter were clear in all of the samples, but only those with blurring showed a dishomogeneous signal in the white matter, with
patchy areas of hyperintensity mainly in the depth of the white matter. Sections from the patients with blurring that were
processed for myelin staining revealed dishomogeneous staining of the white matter, which was confirmed by analyses of the
corresponding semi-thin sections. Ultrastructural examinations revealed the presence of axonal degeneration and a significant
Received November 7, 2011. Revised April 27, 2012. Accepted April 28, 2012.
ß The Author (2012). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
For Permissions, please email: [email protected]
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Rita Garbelli,1 Gloria Milesi,1 Valentina Medici,1 Flavio Villani,1 Giuseppe Didato,1
Francesco Deleo,1 Ludovico D’Incerti,2 Michela Morbin,3 Giulia Mazzoleni,3
Anna Rita Giovagnoli,4 Annalisa Parente,4 Ileana Zucca,4 Alfonso Mastropietro4,5
and Roberto Spreafico1
2
| Brain 2012: Page 2 of 13
R. Garbelli et al.
reduction in the number of axons in the patients with blurring; there were no vascular alterations in either group. These data
obtained using different methodological approaches provide robust evidence that temporo-polar blurring is caused by the
degeneration of fibre bundles and suggest slowly evolving chronic degeneration with the redistribution of the remaining
fibres. The article also discusses the correlations between the morphological findings and clinical data.
Keywords: temporal lobe epilepsy; neuropathology; electron microscopy; high-field MRI; epilepsy surgery
Introduction
Materials and methods
Subjects
The study involved 32 consecutive patients (11 males and 21 females;
mean age: 40 9 years, range: 24–60) with medically intractable temporal lobe epilepsy and radiological evidence of hippocampal sclerosis
who underwent surgery at the Carlo Besta Neurological Institute in
Milan, Italy. Patients with evidence of hippocampal sclerosis associated
with other principal lesions (tumours, vascular malformations and scars
etc.) were excluded.
The findings of studies by Falconer et al. (1964) and Margerison
and Corsellis (1966), reinforced by those of recent MRI studies
(Bernasconi et al., 2000), suggest that hippocampal sclerosis
plays a leading role in the genesis of seizures in patients with
temporal lobe epilepsy. Recent reports indicate that hippocampal
sclerosis is frequently associated with other pathologies (Blumcke
et al., 2002; Tassi et al., 2009), but a number of studies have
shown that even in the absence of a second and independent
principal lesion, the abnormalities found in patients with temporal
lobe epilepsy go beyond the hippocampus, thus suggesting a more
widespread substrate for the generation or persistence of seizures.
MRI has revealed ipsilateral temporal atrophy with temporo-polar
grey/white matter abnormalities in 32–68% of patients with temporal lobe epilepsy and associated hippocampal sclerosis, which
have been described as a loss of grey/white matter demarcation
together with increased signal intensity in T2-weighted images
(Choi et al., 1999; Meiners et al., 1999; Mitchell et al., 1999,
2003; Coste et al., 2002; Adachi et al., 2006). This type of
abnormality (commonly called ‘grey/white matter blurring’) is
described in many articles as one of the most sensitive radiological
markers of focal cortical dysplasia, but some authors suggest that
it may reflect the presence of densely heterotopic neurons in the
subcortical white matter or myelin alterations (Hardiman et al.,
1988; Choi et al., 1999; Meiners et al., 1999; Thom et al., 2001).
Recent imaging techniques have confirmed that the loss of
grey/white matter demarcation in the temporal pole of patients
with temporal lobe epilepsy and hippocampal sclerosis is not due
to imaging artefacts, thus corroborating the hypothesis that epilepsy may depend on a more widespread temporal lobe disturbance (Meiners et al., 1994, 1999; Mitchell et al., 1999; Moran
et al., 2001; Kahane et al., 2002; Bernasconi et al., 2005; Sankar
et al., 2008; Concha et al., 2009). The suggestion that
extra-hippocampal structures (particularly the temporal pole)
may play an important role in patients with temporal lobe epilepsy
and hippocampal sclerosis is supported by electroclinical and perfusion data (Ryvlin et al., 1998, 2002; Mitchell et al., 1999;
Moran et al., 2001; Chassoux et al., 2004; Chabardes et al.,
2005; Weder et al., 2006).
As temporal lobe epilepsy is the most frequent form of
drug-resistant focal epilepsy, surgery is an important and safe
option, allowing patients to gain seizure freedom (Wiebe et al.,
2001), and the increasing numbers of operated subjects with a
good postoperative follow-up have also provided specimens for
precise neuropathological studies and the investigation of anatomo–clinical correlations. However, there is still no consensus
regarding the genesis of these abnormalities, and no definite correlation has yet been found between histopathological findings
and MRI-revealed structural abnormalities, with gliosis (Falconer
et al., 1964), developmental cortical abnormalities (Hardiman
et al., 1988; Thom et al., 2001), myelin loss (Meiners et al.,
1999) and a non-specific increase in temporal lobe water content
(Mitchell et al., 1999; Concha et al., 2009) all being suggested as
possible causes. Furthermore, the question as to whether the grey/
white matter abnormalities revealed by MRI are epileptogenic has
not been answered, although studies by Coste et al. (2002) and
Adachi et al. (2006) argue in favour of an epileptogenic zone
involving the side of the abnormalities. There are also conflicting
data concerning surgical outcomes: Mitchell et al. (1999) found
that the proportion of seizure-free patients was the same in those
with and without grey/white matter abnormalities, whereas Choi
et al. (1999) found a significantly higher success rate in the
patients with abnormalities, although Mitchell’s findings are supported by those of a recent study by Schijns et al. (2011) that
examined the impact of temporal lobe grey/white matter abnormalities on postoperative seizure outcome in patients with temporal
lobe epilepsy and hippocampal sclerosis, undergoing selective
amygdalohippocampectomy or anterior temporal lobectomy. All
of these studies were carried out using traditional methods that
are routinely available in clinical practice, and the results did not
reveal with certainty the aetiology of the temporo-polar abnormalities found in a variable proportion of patients with temporal
lobe epilepsy.
The aim of this study was to investigate the pathological
substrate of the temporo-polar blurring revealed by means of routine clinical 1.5 T MRI using the non-traditional approaches of
high-field (7 T) MRI combined with light and electron microscopy
of surgical specimens taken from drug-refractory patients with
temporal lobe epilepsy and hippocampal sclerosis. The clinical correlations of the abnormalities were also investigated.
Temporo-polar blurring in patients with TLE
The patients underwent surgery after a comprehensive electroclinical
and MRI evaluation; none of them required the invasive presurgical
identification of the epileptogenic zone to be removed.
On the basis of the findings of the presurgical 1.5 T MRI evaluation,
the patients were divided into two groups: 18 with hippocampal sclerosis plus ipsilateral temporo-polar abnormalities (Group 1) and 14 with
hippocampal sclerosis but normal ipsilateral grey/white matter definition in the temporal pole (Group 2). To assess the presence or
absence of these abnormalities, all of the magnetic resonance
images were independently reviewed by two experienced observers
(L.D. and F.V.) blinded to the neuropathological findings, who used
the criteria proposed by Colombo et al. (2009) and issued a consensus
report.
Preoperative 1.5 T magnetic
resonance imaging
Neuropsychological testing
All of the patients underwent a neuropsychological assessment before
surgery and 6 months afterwards. Abstract reasoning, immediate and
long-term memory and verbal fluency were evaluated using Raven’s
Coloured Progressive Matrices, Short Story, Rey’s Complex Figure,
Selective Reminding, Corsi Blocks Supraspan and Word Fluency tests
(Giovagnoli et al., 2011). The controls were 32 healthy subjects
matched in terms of chronological age (mean age: 38.18 11.00
| 3
years), years of schooling (mean age: 12.12 3.38 years) and
gender (21 males, 11 females).
Surgery and follow-up
All of the resections were performed for strictly therapeutic reasons
after the patients had given their informed consent. None of the patients underwent selective amygdalohippocampectomy. The resections
were limited to the temporal lobe in all cases, and their extent was
planned preoperatively on the basis of the location of the epileptogenic zone (as shown by electroclinical data) and the risk of postsurgical deficits. Seizure freedom was monitored periodically and
determined using Engel’s classification (Engel, 1987); only patients
with a minimum follow-up of 12 months were considered.
Histology
Immediately, after surgery, the resected temporal lobes and hippocampi were fixed in 4% paraformaldehyde buffered solution. After
24 h, the temporal lobe specimens were cut into 4–6 coronal slabs
(5 mm thick) throughout its anteroposterior extent and post-fixed in
the same solution for 4–5 days. Alternate slabs were embedded in
paraffin or in 6% agarose to be cut by a vibratome (VT1000S,
Leica). For routine neuropathology, 7-mm thick sections were cut
and stained with thionin (0.1%), haematoxylin and eosin, and
Kluver-Barrera. Additional serial sections were processed for immunohistochemistry using antibodies against glial fibrillary acidic protein
(GFAP; 1:1000 Millipore), non-phosphorylated neurofilaments (SMI
311; 1:250, Sternberger Monoclonals Inc.), neuron-specific nuclear
protein (NeuN; 1:1000; Chemicon International), CD68 (1:1000,
Dako) and fibrinogen (1:600, Dako). Agarose-embedded slabs were
cut into 50-mm thick serial sections, counterstained with thionin and
processed using the primary antibodies and an immunoperoxidase procedure described elsewhere (Garbelli et al., 1999).
Quantification of the degree of gliosis and possible inflammatory
changes in the white matter of all the samples was performed.
Images of sections reacted with the corresponding antibodies; GFAP
and CD68, respectively, were captured with a digital camera in randomly placed visual fields using Image ProPlus 6.3 software (Media
Cybernetics). Gliosis was evaluated considering the intensity of the
colour immunostaining (saturation) in 0.56 mm2 for each case,
whereas CD68-positive cells density was calculated in 0.56 mm2
using a 2D cell-counting technique. The white matter neuronal density
was estimated by counting NeuN-positive neurons in the depth of the
white matter, at least 500 mm from the grey/white matter boundary
(Blumcke et al., 2011), and by two different approaches: a 2D cellcounting technique performed on all samples on representative 2.2
mm2 and, according to the Optical Fractionator technique (West
et al., 1991), with use of the StereoInvestigator software
(Micro-BrightField) in the subgroup of the patients submitted to ultrastructural study (see later). The Optical Fractionator is a stereological
method for estimating the total number of neurons in a region; the
technique combines use of the Optical Disector (a 3D probe for counting neuronal nuclei) and the Fractionator (a systematic random sampling). We considered upper and lower guard zones, corresponding to
the surfaces where the tissue is most affected by sectioning, of 3 mm,
and the square counting frame in the x-y plane was 150 150 mm.
The number of frames ranged from 25 to 36. NeuN-positive nuclei
that came into focus, either fully inside the counting box or touching
the inclusion lines, were counted.
All of the MRI studies were performed using the same 1.5 T instrument
(Siemens Avanto). The MRI protocol included: transverse spin-echo
double-echo images of the entire brain (repetition time: 2000–2500 ms,
echo time: 20–90 ms, number of averages: 1, matrix: 128 256, field of
view: 230 mm, slice thickness: 5 mm); coronal fast spin-echo T2-weighted
images (repetition time: 2300 ms, echo time: 100 ms, number of averages: 4, matrix: 256 256, field of view: 230 mm, thickness: 3 mm);
coronal transverse spin-echo FLAIR images (repetition time: 8000 ms,
echo time: 100 ms, inversion time: 2000 ms, number of averages: 3,
matrix: 238 256, field of view: 230 mm, thickness: 3 mm) and coronal
fast spin-echo inversion recovery T1-weighted images (repetition time:
3000 ms, echo time: 20 ms, inversion time: 400 ms, number of averages:
3, matrix: 256 256, field of view: 230 mm, thickness: 3 mm). The
transversal and coronal sections were acquired parallel and perpendicular,
respectively, to the axis of the hippocampal formation.
No contrast medium was used, and all of the T1- and T2-weighted
images were qualitatively evaluated by means of careful visual inspection in terms of morphology, the thickness and signal intensity of the
cortex of the cerebral hemispheres and the distribution and signal intensity of the white matter. The MRI features of malformed cortical
development, atrophic changes and signal abnormalities in the cortex
and white matter were recorded. Hippocampal sclerosis was qualitatively demonstrated by means of the comparative visual detection of
atrophy and loss of definition of the internal structures of the hippocampal formation and increased signal intensity in the T2-weighted
images. Associated abnormalities of mammillary bodies, the fornix
and the fimbria were also evaluated. Particularly, attention was
given to the interface between the cortex and the underlying white
matter, with the definition of the inner margin of cortical ribbon and
even mild signal abnormalities from the subcortical white matter being
carefully investigated. The morphology and signal intensity of the
grey matter and white matter of the temporal poles were evaluated
on the coronal sections throughout the anteroposterior extent of the
temporal lobe.
4
Finally, to evaluate abnormalities in blood vessel and blood–brain
barrier function, fibrinogen immunoreactivity in all specimens was
performed.
The hippocampi were kept separate and processed for neuropathological diagnosis to confirm the presence of hippocampal sclerosis
(the grading is not considered in this report). The slides were independently reviewed by two neuropathologists, one of whom was unaware of the initial diagnoses and clinical data. Any disagreements
were discussed until an agreed-upon diagnosis had been reached.
The presence of focal cortical dysplasia was diagnosed on the basis
of the new International League Against Epilepsy classification system
(Blumcke et al., 2011) and classified as type IIIa due to the confirmed
neuropathological presence of hippocampal sclerosis.
Correlative 7 T magnetic resonance
imaging and ultrastructural study
200-mesh copper grids (EMS), counterstained with lead citrate and
uranyl acetate and examined using an EM109 electron microscope
(Zeiss). All of the microphotographs were qualitatively evaluated by
two independent and experienced observers (M.M. and G.M.) using a
non-descriptive numerical code. A modified version of the protocol of
Tang et al. (2004) was used for the morphometric analyses. Briefly,
thin sections were cut to avoid overlapping bias, and, starting from a
random mesh of the grid, the two opposite corners of 10 consecutive
fields of each section were photographed at a magnification of
4400. Empty or damaged fields were discarded. A total of 20 digital
images were taken of each area of interest and were analysed by
three independent observers (G.Mi., V.M. and G.Ma.) using a
semi-automatic program (NIS-Elements BR 3.1 Software, Nikon). The
area of each counting frame was 379.21 mm2 and the total examined
area was 7584.2 mm2. The myelinated fibres, on both semi- and
ultra-thin sections, were counted when they were completely inside
the counting frame or partially inside and only touching the counting
lines; they were not counted if they touched the exclusion lines. The
glial and microglial cells, present in some microphotographs, were not
counted, and their presence did not preclude analysis of a microscopy
field. As most of the axons had non-circular profiles, it was not possible to estimate myelin thickness accurately; in these cases, the diameter was measured on the shortest axis of the axonal profile, thus
introducing an uncontrolled bias. The evaluated parameters were the
mean number of axons, axonal density, circularity, elongation, the
circumference and the extra-axonal area. The average parameters of
all of the microphotographs of each patient were used for the statistical analysis.
Statistical analysis
Mean age at epilepsy onset, the duration of epilepsy, age at surgery
and seizure frequency were compared between the two subgroups
using a two-tailed t-test following Levene’s test for equality of variances. The remaining electroclinical features and the presence of blurring were analysed using a contingency table and Fisher’s exact test
(P-values of 50.05 were considered significant).
The neuropsychological test scores of the patient and control group
were compared using the Mann–Whitney test. The significance limit
for seven pairwise comparisons was set at P 5 0.007 (Bonferroni’s
correction). Separate Wilcoxon tests were used to compare the preoperative and 6-month follow-up test scores and regression analyses
to explore the role played by blurring in determining neuropsychological performance.
Differences in mean values of gliosis, neuronal density and CD68positive cells were evaluated between the two subgroups by two-tailed
t-test, whereas differences in the morphometric parameters were assessed by means of one-way ANOVA, followed by individual post hoc
comparisons using Sheffé’s test. A P-value of 50.05 was considered
significant. The Shapiro–Wilk test was used to prove normal data distribution. Statistical analyses were performed using SPSS version 17.
Results
Clinical data and follow-up
The main characteristics of the cohort as a whole are shown in
Table 1. The patients’ mean age at surgery was 40 years [range:
24–60; standard deviation (SD) 9.3], and the mean duration of
epilepsy was 29 years (range: 5–54; SD 14.3). Their mean age at
A subgroup of nine patients (four from Group 1 and five from Group
2) underwent a combined high-field MRI and morphological/ultrastructural study. To this end, one slab from each specimen (corresponding to the anterior part of the temporal lobe and embedded in
6% agarose) was examined by means of experimental MRI using a 7 T
horizontal-bore scanner (BioSpec 70/30 USR, Bruker) equipped with
200 mT/m gradients and a 35-mm transceiver quadrature coil.
High-resolution T2-weighted images were acquired using the parameters: echo time: 50 ms, repetition time: 4.3 s, number of averages: 36,
slice thickness: 0.7 mm, field of view: 32 32 mm2 and data matrix:
256 256, which yielded 73 73 mm2 in-plane resolution. The diffusion tensor imaging acquisitions were carried out using a spin-echo
sequence (echo time: 40 ms, repetition time: 5 s, number of averages:
1, slice thickness: 0.7 mm, field of view: 32 32 mm2, data matrix:
128 128) that yielded a 250 250 mm2 in-plane resolution. The diffusion times were = 22 ms and @ = 12 ms, and there were five b0
images, six directions and seven b-values (800, 1500, 2000, 2500,
3000, 3300 and 3500 s/mm2). Mean diffusivity and fractional anisotropy maps were estimated from the raw data images. The FMRIB
Software Library (www.fmrib.ox.ac.uk/fsl) was used for the tensorial
fitting and for calculating the eigenvalues and eigenvectors.
After MRI, the slabs were cut into 50-mm thick serial coronal sections and processed for: (i) staining with 0.1% thionin for structural
control and Black-GoldÕ II (0.3% dissolved in 0.9% saline,
Histo-Chem) for myelin visualization; (ii) immunohistochemistry as previously described; and (iii) electron microscopy.
One section from each case (chosen from those stained with thionin
and Black-GoldÕ II) was processed for electron microscopy using a
protocol described elsewhere (Garbelli et al., 1999). The osmicated
sections of Group 1 revealed uneven staining, and therefore two
areas of interest in the deep white matter were excised: one corresponding to a lightly stained (light) zone and one corresponding to an
intensely and apparently homogeneously stained (dark) zone. The
osmicated sections of Group 2 showed intense and homogeneous
white matter staining throughout, and therefore only one area was
excised. From each area, 0.5-mm semi-thin sections were cut by means
of an ultramicrotome (Reichert–Jung Ultracut E), mounted on glass
slides and counterstained with toluidine blue for light microscopy
examination. To estimate the number of myelinated fibres in the
white matter, semi-thin sections were observed using an oil objective
lens ( 100, NA 1.32), and two areas of interest from the upper left
and two from under right corners were captured, corresponding to a
final surface of 18 544 mm2 for each sample. Afterwards, ultra-thin
sections (500 Å) representative of the selected areas were placed on
R. Garbelli et al.
| 5
Table 1 Main clinical characteristics of the patients
History
Blurring
No blurring
Total
10 (56)
8.6 (7.0)a
9-9
6 (6.4)
41.4 (9.7)
35.1 (13.6)a
15 (83)
8 (57)
16.9 (7.9)b
7-7
10.9 (9.6)
38.0 (8.7)
21.1 (11.2)b
14 (100)
18 (56)
12.2 (8.4)
16-16
8.1 (8.2)
39.9 (9.3)
29.0 (14.3)
29 (91)
4
7
3
15
15
16
3
16
9
18
17
3
15
8
16
2
8
(22)
(39)
(17)
(83)
(83)
(89)
(17)
(89)c
(50)
(100)
(94)
(17)
(83)
(44)
(89)
(11)
(44)
7
9
4
12
12
10
1
5
5
12
12
2
10
7
13
2
6
(50)
(64)
(29)
(86)
(86)
(71)
(7)
(36)d
(36)
(86)
(86)
(14)
(71)
(50)
(93)
(14)
(43)
11
16
7
27
27
26
4
21
14
30
27
5
25
15
29
4
14
(34)
(50)
(22)
(84)
(84)
(81)
(13)
(66)
(44)
(94)
(84)
(16)
(78)
(47)
(91)
(13)
(44)
a versus b = P 5 0.01.
c versus d = P 5 0.05.
epilepsy onset was 12.2 years (range: 2–35; SD 8.4), and mean
seizure frequency at the time of surgery was 8.1 per month
(range: 1–30; SD 8.2). After 12 months of follow-up (range:
12–60), 29 patients were in Engel’s class I and the remaining
three in class II. The cohort was divided into two groups on the
basis of the presence of blurring in the preoperative magnetic
resonance images (18 patients, 56%) or its absence (14 patients,
44%).
There were no significant between-group differences in terms
of mean age at surgery (P = 0.31), mean seizure frequency
(P = 0.14), the presence of febrile seizures (P = 0.93) or postoperative outcomes (P = 0.11), whereas the patients in Group 1
had a significantly younger mean age at epilepsy onset (P = 0.004)
and significantly longer mean duration of epilepsy (P = 0.004).
A review of the seizure semiology and the video-EEG data
showed that the only significant difference between the two
groups was the presence of contralateral dystonia during seizures,
which was observed in 89% of the patients of the Group 1 and
36% of those in Group 2 (P = 0.028) (Table 1).
Preoperative magnetic
resonance imaging
The FLAIR and T2-weighted images of all of the patients in Group
1 (nine left, nine right) showed hyperintensity in the white matter
of the temporal pole ipsilateral to the hippocampal sclerosis. The
intensity of the white matter signal was similar to that of the grey
matter, with a blurred grey/white matter junction in the temporal
pole and ipsilateral hypoplasia of the temporal pole in 13 subjects
(72%; Figs 1A–G and 2A). In Group 2 (seven left, seven right),
normal and homogenous signal intensity was observed throughout
the temporal lobe white matter, and the grey/white matter interface was clearly defined (Fig. 2D); only two cases (1.5%) showed
ipsilateral hypoplasia of the temporal pole. No signal abnormalities
and no ipsilateral atrophy of the fornix, fimbria or mammillary
bodies were detected in any of the 32 patients.
Of the nine cases selected for correlative imaging and electron
microscopy study, atrophy of the temporal pole ipsilateral to the
hippocampal sclerosis was observed in two patients in Group 1
and two in Group 2.
Neuropsychology
With respect to the controls, patients with blurring were significantly impaired at all of the neuropsychological tests, whereas
non-blurring patients were significantly impaired in Short Story
and Word Fluency on phonemic and semantic cues. Blurring patients also showed lower Raven’s Coloured Progressive Matrices
scores than non-blurring patients. The presence of blurring predicted the preoperative score on Raven’s Coloured Progressive
Matrices (r2 = 0.16, F = 5.16, P = 0.03) (Table 2). There were no
History
Febrile seizure (%)
Mean age at epilepsy onset (SD)
Side of surgery (right-left)
Mean monthly seizure frequency at surgery (SD)
Mean age at surgery (SD)
Mean duration of epilepsy (SD)
Class I after surgery (%)
Seizure semiology and video-EEG
Convulsive seizures (%)
Morpheic seizures (%)
Fallings (%)
Verbal alert (%)
Oroalimentary automatisms (%)
Manual automatisms (%)
Bipedal automatisms (%)
Contralateral dystonia (%)
Omolateral head turning (%)
Awareness of the seizure (%)
Localized interictal abnormalities (%)
Contralateral interictal abnormalities (%)
Localized ictal EEG (%)
Low-voltage fast activity (%)
Mesial temporal seizure pattern (%)
Neocortical temporal seizure pattern (%)
Contralateral diffusion of ictal activity (%)
6
R. Garbelli et al.
The coronal T2-weighted (A) and FLAIR (B) images show atrophy and signal hyperintensity in the left hippocampal formation; the
axial section (C) also shows atrophy of the temporal pole. Blurring of the ipsilateral temporal pole can be seen in contiguous T2-weighted
(D and E) and FLAIR images (F and G); note the signal hyperintensity of the white matter (asterisks) in the left temporal pole, with an
ill-defined grey/white matter junction.
significant postoperative changes and no differences related to the
side of the epileptic region in either group.
Histology
The diagnosis of hippocampal sclerosis was confirmed in all 32
patients. Architectural abnormalities in the temporal cortex, characterized by the blurred demarcation of the layers (type IIIa focal
cortical dysplasia), were diagnosed in 15 of the 18 patients in
Group 1 (83%) and 13 of the 14 patients in Group 2 (93%).
Moreover, five patients in Group 1 and three in Group 2
showed temporal lobe sclerosis (Thom et al., 2009), a variant of
type IIIa focal cortical dysplasia that is characterized by an atypical
band of clustered neurons in the outer part of layer 2 and neuronal depletion in layers 2–3 (Supplementary Fig. 1A and B). In all
cases, regardless of the presence/absence of blurring, a variable
degree of gliosis of the white matter was evident on GFAP immunostaining, and CD68-positive cells were encountered in all the
surgical samples diffusely distributed in the white matter and
sometimes located around vessels. According to these observations, quantitative analysis of the GFAP staining intensity and
CD68-positive cell density in the white matter revealed no differences between the two groups (P = 0.30 for GFAP and P = 0.19
for CD68, Supplementary Fig. 1C and D). The presence of an
Figure 1 Presurgical (1.5 T) magnetic images of a patient with left hippocampal sclerosis plus ipsilateral temporo-polar abnormalities.
| 7
Table 2 Preoperative neuropsychological test scores in patients and controls
Blurring
versus no
blurring*
Blurring
versus
controls*
No blurring
versus
controls*
33.46 (19–46)
42.45 (14–57)
NS
9.29 (3–19.5)
10.92 (4.5–19)
15.61 (9–24.5)
NS
Selective reminding procedure
91.53 (13–169)
118.27 (0–163)
125.46 (28–166)
NS
Rey complex figure delayed
reproduction
Corsi blocks supraspan learning
15.44 (8–25)
18.98 (7–35)
20.81 (9–32)
NS
16.73 (6.18–27.84)
20.45 (7.32–28.72)
25.70 (18.42–18.94)
NS
U = 111,
P 5 0.001
U = 113,
P = 0.001
U = 95.5,
P 5 0.001
U = 82,
P 5 0.001
U = 115,
P = 0.019
U = 164.5,
P = 0.008
U = 47.5,
P 5 0.001
NS
39.45 (21–65)
U = 51,
P = 0.01
NS
Neuropsychological test
Blurring
Mean (range)
Raven coloured progressive
matrices
Word fluency on phonemic cue
28.82 (21–35)
32.31 (28–36)
32.79 (20–36)
26.35 (13–46)
25.92 (12–45)
Word fluency on semantic cue
32.18 (19–45)
Short story
NS = not significant; *Mann–Whitney tests.
No blurring
Mean (range)
Controls
Mean (range)
U = 94,
P = 0.003
U = 94,
P = 0.003
U = 94.5,
P = 0.003
NS
NS
NS
Figure 2 Comparison of presurgical 1.5 (A and D) and ex vivo 7 T magnetic resonance images (B and E) of patients with (A and B) and
without blurring (D and E). In the T2-weighted images obtained from the surgical samples of both groups, the boundary between the grey
matter and white matter was always clear (compare B and E, arrows), whereas signal intensity in the white matter was dishomogeneous
and showed patchy areas of hyperintensity (asterisks) only in the samples taken from patients with blurring. The fractional anisotropy
maps show lower values in the white matter of the patients (compare C and F), thus suggesting the loss of white matter integrity.
8
excess of single white matter neurons was frequently observed in
all samples, and their density was estimated in both groups. We
found a wide range of white matter neuronal density using both
2D (30–94 neurons/mm2 in Group 1 and 21–59 neurons/mm2 in
Group 2) and 3D cell-counting techniques (1777–3504 neurons/
mm3 in Group 1 and 1636–4243 neurons/mm3 in Group 2), but
no significant differences in the average density between the two
groups was observed (P = 0.22 and P = 0.54, Supplementary Fig.
1E and F). Blood vessels and, when present, perivascular spaces
were intensely stained by fibrinogen immunoreactivity in all samples from both groups (Supplementary Fig. 1G and H).
Correlative 7 T magnetic resonance
imaging and ultrastructural study
represented a smaller fraction of the entire area of the Group 1
samples (particularly in the light zone), thus leading to a larger
extra-axonal area (86% and 83% in the light and dark zones of
the Group 1 samples, respectively, versus 79% of the Group 2
samples).
Discussion
The MRI features of the anterior temporal signal abnormalities
commonly called ‘blurring’ consist of a less marked definition of
the grey/white matter border, frequently coupled with the apparent shrinkage of the white matter core of the temporal pole. They
have long been described in a subgroup of patients with temporal
lobe epilepsy, and the prevalence of ipsilateral anterior temporal
abnormalities in patients with intractable temporal lobe epilepsy
and hippocampal sclerosis has been estimated as being 32–66%
(Choi et al., 1999; Meiners et al., 1999; Mitchell et al., 1999) in
adults and 57% in children (Mitchell et al., 2003). During the past
10 years, numerous attempts have been made to assess the aetiopathogenesis of temporo-polar blurring, but none of the various
hypotheses has been confirmed, which means that although the
MRI appearance may reflect a change in the water content of the
temporal lobe, the pathological substrate of the change is still
unknown. We used different methodological approaches to collect
robust evidence that the blurring is caused by fibre bundle degeneration and will discuss here the morphological data and their
possible clinical implications separately.
Temporo-polar blurring and white
matter fibre degeneration
It has been suggested that temporo-polar blurring is due to
vasculometabolic disturbances in the temporal lobe that are presumably secondary mechanisms of repetitive seizures (Ryvlin et al.,
1998; Weder et al., 2006). Further, Chassoux et al. (2004) found
that temporal hypometabolism was more extended in patients
with temporo-polar signal changes. We therefore assumed that,
if the blurring is due to functional vasculometabolic mechanisms, it
would no longer be visible on magnetic resonance images of surgically removed and fixed temporal lobe samples; however, we
found that signal alterations could still be seen in our Group 1
specimens.
Nevertheless, there were some differences between the presurgical 1.5 T magnetic resonance images and the 7 T images of the
surgical specimens. In Group 1, the grey/white matter border was
clearly marked, but signal alterations were particularly pronounced
in the deep white matter; furthermore, the hyperintense signal
was frequently dishomogeneous and there were patchy areas of
different intensities. The differences between the 1.5 and 7 T
images may be due to the higher resolution of the latter (which
is also due to the number of repetitions allowing the use of thinner
sections) or to the fixation procedures. However, the second hypothesis can be ruled out because we have previously shown that
fixation procedures do not substantially alter 7 T images, which are
comparable with those obtained in vivo using a 1.5 T machine
(Garbelli et al., 2011).
Unlike the in vivo T2-weighted images (Fig. 2A and D), there was
a clear border between the grey and white matter in all of the
samples (Figs 2B and E, 3A and I and 4A). However, signal intensity in the white matter was dishomogeneous in the Group 1
samples, with patchy areas of hyperintensity mainly in the depth
(Figs 2B, 3A and I), whereas visual analysis of the Group 2 images
showed a homogeneous hypointense signal throughout the white
matter (Figs 2E and 4A). The fractional anistropy maps obtained
from the same specimens showed similar grey matter values in
both groups, whereas the white matter fractional anistropy
values were lower in Group 1 (compare Fig. 2C with Fig. 2F).
The mean diffusivity values did not reveal any clear betweengroup differences in either the white matter or the grey matter
(data not shown).
After the imaging study, the specimens underwent morphological/ultrastructural study. The Group 1 sections processed for
Black-GoldÕ II revealed dishomogeneous staining in the white
matter, whereas the same staining was homogeneous in the
Group 2 sections (compare Fig. 3B, C, E, J, K and M with
Fig. 4B and C). Analysis of the adjacent semi-thin sections counterstained with toluidine blue confirmed this difference (compare
Fig. 3D, F, L and N with Fig. 4D). The qualitative ultrastructural
examination showed that the samples from Group 1 (particularly
those from the light zone) had more extra-axonal space, fewer
myelinated and unmyelinated axons, which also varied considerably in size and morphology in comparison with the Group 2
samples (compare Fig. 3G, H, O and P with Fig. 4E and F). Glial
cells, glial processes and vacuoles of different size were also
observed in the neuropil. On the contrary, the specimens of
both groups showed no alterations in myelin sheath thickness in
relation to axonal diameter and no alterations in the vessels walls.
In particular, there were no desmosome alterations in the capillary
endothelial cells and no alterations in the elastic and muscular
tunica of the arteriolar walls. Quantitative analyses confirmed
that the number of axons and axonal density in the white
matter were significantly reduced in both the light and dark
zones of the Group 1 samples, with no differences between the
zones (Table 3). Moreover, the myelinated axons were less circular
and more elongated than those in the Group 2 samples, thus
indicating a tendency towards tilted axons, and their circumference was larger. The cumulative area occupied by axons
R. Garbelli et al.
| 9
Figure 3 Correlative data from the 7 T magnetic resonance, histochemical and ultrastructural images of two patients with blurring.
The dishomogeneous signal intensity in the white matter revealed by the T2-weighted images (A and I) correlates with the
dishomogeneous staining of the myelinated fibres clearly visualized by means of Black-GoldÕ (B and J). The high-magnification images C,
K, E and M show the distribution of the myelinated fibres in a lightly stained zone (yellow asterisks) and an intensely stained zone
(green asterisks), respectively. Adjacent 0.5-mm semi-thin sections counterstained with toluidine blue (D, F, L and N). Electron micrographs
(G, H, O and P) obtained from the lightly stained (yellow bordered panel) and intensely stained zone (green bordered panel). The
ultrastructure images clearly show a reduced number of axons in all of the sampled areas (compare with Fig. 4E and F), with a normal
myelin sheath and increased extra-axonal spaces with vacuoles. Scale bars: 45 mm (C, E, K and M); 25 mm (D, F, L and N); 0.6 mm (G, H, O
and P).
10
R. Garbelli et al.
homogeneous signal intensity in the white matter revealed by the T2-weighted images (A) and the homogeneous staining of the
myelinated fibres obtained from a section stained with Black-GoldÕ (B); the asterisk indicates the area shown at higher magnification in C.
D, E and F show adjacent 0.5-mm semi-thin sections counterstained with toluidine blue and electron micrographs. Note the larger number
of axons and fewer extra-axonal spaces in comparison with the patients with blurring (compare with Fig. 3G, H, O and P). Scale bars:
45 mm (C), 25 mm (D); 0.6 mm (E and F).
Table 3 Quantitative analysis of the morphometric parameters performed on semi-thin and ultra-thin sections
Evaluated parameters
Blurring
No blurring
Mean (SD)
Mean (SD)
Light zone
Number of axon (OM)
Axonal density (axons/mm2) (OM)
Circularity (EM)
Elongation (EM)
Circumference (EM)
Area occupied by axons (mm2) (EM)
Dark zone
a
2234 (294)b
0.120 (0.015)b
0.64 (0.079)
2.21 (0.24)
4.15 (0.83)
1319 (185)
2174 (599)
0.117 (0.003)a
0.64 (0.059)
2.14 (0.26)
3.93 (0.84)
1055 (166)d
3506 (591)c
0.189 (0.032)c
0.70 (0.079)
1.90 (0.18)
3.11 (0.67)
1588 (83)e
a, b versus c = P 5 0.05.
d versus e = P 5 0.01.
EM = electron microscopy, ultra-thin sections; OM = light miscrosopy, semi-thin sections.
The findings also rule out the hypothesis that the signal alterations have a vasculometabolic origin and support the hypothesis
of structural morphological alterations. Some authors have suggested that blurring might be caused by abnormalities in structural
development (Hardiman et al., 1988; Thom et al., 2001), but our
histopathological study revealed that patients with and without
blurring may have similar neuropathological features, such as the
presence of a cortical dysplasia and an excess of single white
matter neurons, thus excluding their potential involvement.
Other explanations of blurring are dilated perivascular spaces
and inflammatory changes, but Mitchell et al. (1999) found that
all of these minor changes are common regardless of the presence
or absence of MRI blurring. Although we did not make a similarly
precise analysis, our study did not reveal any difference in inflammatory changes or any significant alterations in blood vessels.
The presence of widespread gliosis has also been considered to
explain the MRI abnormalities, but no differences have been
found in the density of glial cell nuclei in the temporal white
matter between patients with and without blurring (Meiners
et al., 1999; Mitchell et al., 1999), although our findings are in
line with these reports, as they also show considerable variability in
the degree of gliosis detected by means of GFAP staining within
and between the groups. However, dishomogeneous myelin staining indicated clear fibre alterations that correlated with the 7 T
images, thus supporting a hypothesis that has been previously
proposed on the basis of the findings of neuropathological investigations (Meiners et al., 1999; Mitchell et al., 1999; Schijns et al.,
2011) and modern imaging studies (Concha et al., 2009).
Meiners et al. (1999) found significantly reduced white matter
staining, suggesting myelin loss in patients with MRI signal
Figure 4 Correlative 7 T magnetic resonance, histochemical and ultrastructural images of one patient without blurring. Note the
| 11
In a recent study, Concha et al. (2009) found a correlation
between electron microscopy and in vivo diffusion tensor imaging
findings that validated diffusion tensor imaging findings as an
in vivo marker of white matter pathology. Our results show that
even in surgical specimens, fractional anistropy is altered in patients with temporal lobe epilepsy and hippocampal sclerosis, thus
further confirming the correlation between altered MRI signals and
neuropathological white matter alterations at light and ultrastructural level. Abnormalities in structures other than the white matter
bundles in the temporal pole were not detected in the routine
1.5 T MRI of our patients, and so the alterations in other fibre
bundles reported by other authors might have been missed.
However, it needs to be emphasized that we only considered
temporo-polar abnormalities and the histopathological correlations
of pre- and post-surgical images. Our study confirmed that
high-resolution MRI and diffusion tensor imaging can also be performed on well-preserved and fixed surgical specimens (Garbelli
et al., 2011).
Clinical correlations
Although anamnestic records of epilepsy risk factors (particularly
febrile seizures) have to be considered with caution, our data do
not suggest any correlation between febrile seizures and the presence of white matter abnormalities, in line with previous reports
(Mitchell et al., 2003; Schijns et al., 2011). As focal cortical dysplasia or heterotopic neurons in the white matter were equally
distributed in both groups, they cannot be considered responsible
for the temporo-polar abnormalities, which are also not associated
with the type or frequency of the seizures.
Our data confirm that patients with white matter abnormalities
in the temporal pole are significantly younger at the time of seizure onset than those without abnormalities. Mitchell et al. (2003)
found a significant relationship between anterior temporal changes
and epilepsy onset before the age of 2 years in their paediatric
population, and the population described by Schijns et al. (2011)
showed that a significant percentage of patients had a mean age
of 2 years at onset; however, studies of adult (or mixed) populations such as ours indicate a mean age of 7–8 years at onset. The
difference in age at seizure onset in the group with blurring may
be due to the fact that, as stated by Mitchell et al. (2003), ‘details
of the change early in the patients’ history are often more vague
when obtained in adulthood and early details not well
remembered’.
All of the published studies report possible myelin alterations
with an early age of epilepsy onset, but our data show massive
axonal loss and preserved myelin in the residual axons, which
suggests an early degenerative process involving some but not
all of the fibres within the temporal lobe white matter. The disappearance of selected axonal tract(s) might be secondary to a
dysmyelination process caused by repetitive abnormal firing within
the temporal lobe, a hypothesis that is supported by findings
showing that axonal myelination at least partially depends on signals of axon origin, and that factors inducing myelin formation are
mediated by electrical activity (Lubetzki and Stankoff, 2000). It is
well known that major events in myelination processes occur
within the first 2 years of life, even if more subtle changes
alterations, and therefore postulated that decreased myelin density
in the temporal lobe of hippocampal sclerosis patients may be due
to the trans-synaptic retrograde degeneration of collaterals of afferent axons in association bundles. Schijns et al. (2011) suggested
that loss of the grey matter border may be a persistent immature
appearance due to abnormal or delayed myelination during
development.
Our morphological data demonstrate that the number of
fibres in the subcortical white matter of the patients in Group 1
was significantly reduced and that the percentage of the area
occupied by myelinated axons was smaller in comparison with
Group 2 patients. Consequently, the residual fibres are less circular, more elongated and wider presumably because of a spatial
rearrangement.
Interestingly, the residual myelinated fibres did not show any
substantial alteration in the myelin sheath or any signs of inflammatory processes and remyelination. As demyelination is characterized by the destruction of normally formed myelin and is often
followed by remyelination associated with signs of inflammation,
our morphological data seem to argue against this type of pathological process and, in line with the suggestion of Schijns et al.
(2011), we believe that the term ‘dysmyelination’ (characterized
by the defective biosynthesis and formation of myelin sheaths)
would be more appropriate in such cases. However, whatever
the mechanism may be, our data demonstrate massive axonal
loss and a redistribution of the remaining fibres that is similar to
that observed in chronic degeneration processes.
The light and electron microscopy neuropathological data agree
with the MRI findings and show decreased fractional anistropy
values in Group 1. Although volumetric MRI has demonstrated
extensive white matter abnormalities in patients with temporal
lobe epilepsy, it is considered a non-specific measure, and therefore, new imaging techniques such as diffusion tensor imaging
have been increasingly used for the past few years to characterize
white matter architecture in vivo and have provided information
about the integrity and organization of fibre tracts. In particular,
diffusion tensor imaging has been extensively used on the basis of
the assumption that in vivo diffusion tensor imaging abnormalities
reflect underlying changes in white matter microstructure.
However, although data from animal models and post-mortem
human brains have given insights into the histological correlates
of diffusion tensor imaging parameters, there are still considerable
limitations when drawing conclusions regarding the underlying
microstructural features associated with human in vivo diffusion
tensor imaging findings (D’Arceuil et al., 2007). Among the various proposed indices, fractional anisotropy is most frequently used
to quantify the direction of diffusion and therefore the structural
integrity of tissue. Decreased fractional anisotropy values indicating a loss of white matter integrity have been found in the ipsilateral temporal lobe, the cingulum, the corpus callosum and the
external capsule of patients with temporal lobe epilepsy and hippocampal sclerosis (Arfanakis et al., 2002; Gross et al., 2006;
Concha et al., 2007; Focke et al., 2008), but the cause of these
changes is still debated, although tissue oedema, blood–brain barrier disturbances, neuronal loss and axonal demyelination have all
been postulated (Margerison and Corsellis, 1966; Bernasconi
et al., 1999; Sutula et al., 2003; Seidenberg et al., 2005).
12
Acknowledgements
The authors thank Dr C. Marras, neurosurgeon at the Fondazione
IRCCS, Istituto Neurologico ‘C. Besta’, for providing the surgical
samples and Prof A. Vercelli and Dr M. Boido at the Department
of Anatomy, Pharmacology and Forensic Medicine, Neuroscience
Institute of the Cavalieri Ottolenghi, University of Turin, Orbassano,
Italy for their help in stereological analysis. We are also grateful to
Prof. M. Bentivoglio for critically reading the manuscript.
Funding
Italian Ministry of Health; the EU Functional Genomics and
Neurobiology of Epilepsy-EPICURE (Grant no. LSHM-CT-20060373315); the Associazione P. Zorzi per le Neuroscienze and the
Fondazione Banca del Monte di Lombardia (FBML).
Supplementary material
Supplementary material is available at Brain online.
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Blurring in patients with temporal lobe epilepsy: clinical, high

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